Bethel C A, Murugesh D, Harrison M R, Mohandas N, Rubin E M
Life Sciences Division, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.
Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10120-4. doi: 10.1073/pnas.90.21.10120.
We have explored the application of fetal hematopoietic stem cell (HSC) transplants for cellular replacement in a murine model of beta-thalassemia. Liver-derived HSCs from nonthalassemic syngeneic murine fetal donors were transplanted into nonirradiated neonatal beta-thalassemic recipients. Significant erythrocyte chimerism (9-27%) was demonstrated in the majority of recipients at 1 month and remained stable or increased (up to 55%) during long-term follow-up in almost all cases. Chimeras had improved phenotypes, as evidenced by decreased reticulocyte counts, increased mean erythrocyte deformability, and decreased iron deposits in comparison to controls. To investigate whether the high degree of peripheral blood chimerism was predominantly a feature of erythroid elements or was a general feature of all hematopoietic elements, chimeras were created using donor HSCs "tagged" with a DNA transgene. Whereas donor hemoglobin comprised > 30% of total hemoglobin, nucleated tagged nonerythroid donor cells comprised < 1% of peripheral blood elements. Explanations for the observed selective increase in erythroid chimerism include longer survival of normal donor red cells compared to that of thalassemic red cells and the effective maturation of the donor erythroid elements in the bone marrow in chimeric animals. The latter explanation bears consideration because it is consistent with the process of ineffective erythropoiesis, well documented to occur in thalassemia, in which the majority of thalassemic erythroid cells are destroyed during erythropoiesis prior to release from the bone marrow. Overall, these data demonstrate the potential for significant erythroid chimerism and suggest that fetal HSC transplantation may play a significant role in future treatment.
我们在β地中海贫血小鼠模型中探索了胎儿造血干细胞（HSC）移植用于细胞替代的应用。将来自同基因非地中海贫血小鼠胎儿供体的肝脏来源的HSC移植到未受照射的新生β地中海贫血受体中。在大多数受体中，1个月时出现了显著的红细胞嵌合现象（9 - 27%），并且在几乎所有病例的长期随访中保持稳定或增加（高达55%）。与对照组相比，嵌合体的表型有所改善，表现为网织红细胞计数减少、平均红细胞变形性增加以及铁沉积减少。为了研究外周血高度嵌合现象主要是红系成分的特征还是所有造血成分的普遍特征，使用带有DNA转基因“标记”的供体HSC创建了嵌合体。虽然供体血红蛋白占总血红蛋白的> 30%，但有核标记的非红系供体细胞在外周血成分中占< 1%。观察到的红系嵌合选择性增加的解释包括正常供体红细胞比地中海贫血红细胞存活时间更长，以及嵌合动物骨髓中供体红系成分有效成熟。后一种解释值得考虑，因为它与地中海贫血中记录充分的无效红细胞生成过程一致，在地中海贫血中，大多数地中海贫血红系细胞在从骨髓释放之前的红细胞生成过程中被破坏。总体而言，这些数据证明了显著红系嵌合的潜力，并表明胎儿HSC移植可能在未来治疗中发挥重要作用。
